Dissecting PKA activation of mTORC1 and its function in adipose tissue
剖析 mTORC1 的 PKA 激活及其在脂肪组织中的功能
基本信息
- 批准号:10091138
- 负责人:
- 金额:$ 6.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-22 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdipocytesAdipose tissueAlanineAmino AcidsAntibodiesAreaAspartateBehavioralBiochemicalBiogenesisBiologicalBody fatBody mass indexBrown FatCRISPR/Cas technologyCaloriesCatecholaminesCell Culture TechniquesCell modelCellsChronic DiseaseClinicalClothingComplexCountryCyclic AMPCyclic AMP Receptor ProteinCyclic AMP-Dependent Protein KinasesDataData SetDesire for foodDevelopmentDiseaseEndocrine System DiseasesEnergy MetabolismEngineeringEpidemicEventFDA approvedFRAP1 geneFatty AcidsFatty acid glycerol estersFollow-Up StudiesGenerationsGenesGeneticGenetic TranscriptionGlucoseGoalsGrowth FactorHumanIn VitroInsulinInsulin ResistanceInterventionInvestigationKnock-inKnowledgeLaboratory AnimalsLife StyleLipolysisLongevityMechanicsMetabolicMetabolic DiseasesMetabolic syndromeMetabolismMitochondriaMitogen-Activated Protein KinasesModelingMolecularMusMutationNon-Insulin-Dependent Diabetes MellitusObesityOverweightPPAR gammaPathway interactionsPeripheralPhosphoproteinsPhosphorylationPhosphorylation SitePhosphotransferasesPhysiologicalPopulationProcessProductionProteinsProteomicsProtonsPublic HealthRaptorsReceptor ActivationRegulationResistanceRespirationRibosomal Protein S6 KinaseRiskRodentRoleRouteSafetyScanningSignal PathwaySignal TransductionSirolimusSiteSourceStable Isotope LabelingSympathetic Nervous SystemTechniquesTechnologyTestingTherapeuticThermogenesisTissuesWeight GainWorkabsorptionbeta-adrenergic receptorcell typecomorbiditycomparativecostexperimental studyfat burningfightinggain of functiongain of function mutationhealth economicsimprovedin vivoinhibitor/antagonistinsightinsulin sensitivitykinase inhibitorloss of function mutationnovelnovel strategiesobesity treatmentp38 Mitogen Activated Protein Kinasephosphoproteomicspreventprogramsreconstitutiontransdifferentiationuncoupling protein 1
项目摘要
Project Summary:
Obesity is at epidemic proportions in the US. Over 60% of the population is either overweight (Body Mass
Index [BMI] ≥25 to <30 kg/m2) or obese (BMI ≥30 kg/m2), placing them at risk for a large number of chronic
diseases, including insulin resistance, metabolic syndrome, and type 2 diabetes. The annual costs of obesity
exceed $100 billion, making it one of the most significant public health and economic issues facing the country.
Unfortunately, the treatment of obesity is unsatisfactory. Lifestyle and behavioral approaches have a modest,
and often transient, effect while FDA-approved therapeutic options targeting appetite or fat absorption have
poor tolerability and, in some cases, safety concerns. Thus, there is a critical need for novel approaches to
treat obesity. Agents acting via peripheral mechanisms to increase energy expenditure would be valuable. The
sympathetic nervous system (SNS) is well-known as an activator of brown adipose tissue (BAT) and the
“browning” of cells in white adipose tissue (WAT) depots to increase uncoupled mitochondrial respiration and
energy expenditure. Our earlier work established a signaling cascade from β-adrenergic receptors (βARs)
cAMP protein kinase A (PKA) p38 MAP kinase (MAPK) to drive the transcription of brown adipocyte
genes such as uncoupling protein-1 (UCP1), PPAR-gamma coativator-1α (PGC-1α), and the broader program
of mitochondrial biogenesis.
We have discovered that the mTOR complex-1 (mTORC1) components mTOR and Raptor are phosphorylated
by PKA. This is a highly novel observation, since the `canonical' pathway to mTORC1 is through growth
factors and insulin. From in vivo studies in mice we find that blockade of mTORC1 with rapamycin, or genetic
deletion of Raptor specifically in adipose tissue, suppresses the ability of the βAR pathway in increase the
amount of UCP1-expressing `beige' adipocytes within white fat depots, and dampens UCP1 expression and
respiration in interscapular brown fat. The ability of laboratory animals and humans to expand these `beige'
adipocytes is closely correlated with resistance to weight gain and improved insulin sensitivity.
We have identified the phosphorylation sites on mTOR and Raptor and propose to test the physiological
consequences of cells and mice in which Ser791 of Raptor is changed to either Alanine (loss-of-function
mutation) or Aspartate (gain-of-function) by engineering a `knock-in' genetic construct. Since we now show that
there are two distinct routes to activation of mTORC1, we are also taking an unbiased proteomic approach to
identify the unique phosphorylation substrates of mTOR resulting from PKA activation vs insulin. Altogether,
these experiments will shed important mechanistic and physiological insight into the steps needed for `beige'
cell expansion, as well as the broader ability of the PKA mTORC1 pathway to function in other cell types.
项目总结:
在美国,肥胖症的流行程度很高。超过60%的人口要么超重(身体质量
体重指数[BMI]≥25至30 kg/m2)或肥胖(BMI≥30 kg/m2),使他们面临患上大量慢性
疾病,包括胰岛素抵抗、代谢综合征和2型糖尿病。肥胖症的年度成本
超过1000亿美元,使其成为该国面临的最重要的公共卫生和经济问题之一。
不幸的是,肥胖症的治疗并不令人满意。生活方式和行为方式有适度的,
通常是暂时的,而FDA批准的针对食欲或脂肪吸收的治疗方案有
耐受性差,在某些情况下,安全问题。因此,迫切需要新的方法来
治疗肥胖症。通过外围机制来增加能量消耗的代理将是有价值的。这个
交感神经系统(SNS)是众所周知的棕色脂肪组织(BAT)的激活剂,而
白色脂肪组织(WAT)储存库中细胞的“褐变”,以增加未偶联的线粒体呼吸和
能源支出。我们早期的工作建立了β-肾上腺素能受体(β-AR)的信号级联
CAMP-蛋白激酶A--p38-MAPK对棕色脂肪细胞转录的影响
解偶联蛋白-1(UCP1)、PPAR-γ衣壳蛋白-1α(PGC-1α)等基因,以及更广泛的程序
线粒体的生物发生。
我们发现mTOR复合体-1(MTORC1)成分mTOR和Raptor被磷酸化
由PKA提供。这是一个非常新奇的观察结果,因为通向mTORC1的典型途径是通过生长。
因子和胰岛素。在小鼠体内的研究中,我们发现用雷帕霉素或基因阻断mTORC1
脂肪组织中特异的Raptor基因的缺失,抑制了βAR途径增加
白色脂肪库中表达UCP1的“米色”脂肪细胞的数量,并抑制UCP1的表达和
肩胛骨间棕色脂肪的呼吸。实验动物和人类扩大这些“米色”的能力
脂肪细胞与抵抗体重增加和改善胰岛素敏感性密切相关。
我们已经确定了mTOR和Raptor上的磷酸化位点,并建议测试生理上的
在细胞和小鼠中,Raptor的Ser791改变为丙氨酸(功能丧失)的后果
突变)或天冬氨酸(功能获得)通过设计“Knock-in”基因结构。既然我们现在展示的是
有两种不同的途径可以激活mTORC1,我们也采取了一种公正的蛋白质组学方法来
确定由PKA激活和胰岛素引起的mTOR的独特的磷酸化底物。总而言之,
这些实验将为“米色”所需的步骤提供重要的机械学和生理学见解。
细胞扩增,以及PKAmTORC1通路在其他细胞类型中发挥作用的更广泛的能力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SHEILA COLLINS其他文献
SHEILA COLLINS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('SHEILA COLLINS', 18)}}的其他基金
Role of SIK3 in PKA/mTORC1 regulation of adipose browning
SIK3 在 PKA/mTORC1 调节脂肪褐变中的作用
- 批准号:
10736962 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Natriuretic peptide and cGMP signaling in adipose tissue and energy metabolism
脂肪组织和能量代谢中的利钠肽和 cGMP 信号传导
- 批准号:
10445966 - 财政年份:2022
- 资助金额:
$ 6.52万 - 项目类别:
Pathophysiology of Metabolically Detrimental Changes in Adipose Distribution, Adipocyte Function, and Adipose Immune Environment on Antiretroviral Therapy
抗逆转录病毒治疗中脂肪分布、脂肪细胞功能和脂肪免疫环境代谢有害变化的病理生理学
- 批准号:
10570223 - 财政年份:2022
- 资助金额:
$ 6.52万 - 项目类别:
Pathophysiology of Metabolically Detrimental Changes in Adipose Distribution, Adipocyte Function, and Adipose Immune Environment on Antiretroviral Therapy
抗逆转录病毒治疗中脂肪分布、脂肪细胞功能和脂肪免疫环境代谢有害变化的病理生理学
- 批准号:
10364376 - 财政年份:2022
- 资助金额:
$ 6.52万 - 项目类别:
Natriuretic peptide and cGMP signaling in adipose tissue and energy metabolism
脂肪组织和能量代谢中的利钠肽和 cGMP 信号传导
- 批准号:
10609907 - 财政年份:2022
- 资助金额:
$ 6.52万 - 项目类别:
Regulation of Natriuretic Peptide Signaling in Adipose Tissue and Energy Metabolism
脂肪组织和能量代谢中钠尿肽信号传导的调节
- 批准号:
10246562 - 财政年份:2020
- 资助金额:
$ 6.52万 - 项目类别:
Dissecting PKA activation of mTORC1 and its function in adipose tissue
剖析 mTORC1 的 PKA 激活及其在脂肪组织中的功能
- 批准号:
9768476 - 财政年份:2018
- 资助金额:
$ 6.52万 - 项目类别:
Dissecting PKA activation of mTORC1 and its function in adipose tissue
剖析 mTORC1 的 PKA 激活及其在脂肪组织中的功能
- 批准号:
10219236 - 财政年份:2018
- 资助金额:
$ 6.52万 - 项目类别:
Natriuretic peptide receptors, adipose browning and energy expenditure
利钠肽受体、脂肪褐变和能量消耗
- 批准号:
8768157 - 财政年份:2014
- 资助金额:
$ 6.52万 - 项目类别:
Natriuretic peptide receptors, adipose browning and energy expenditure
利钠肽受体、脂肪褐变和能量消耗
- 批准号:
8860180 - 财政年份:2014
- 资助金额:
$ 6.52万 - 项目类别:
相似海外基金
Deciphering the role of adipose tissue in common metabolic disease via adipose tissue proteomics
通过脂肪组织蛋白质组学解读脂肪组织在常见代谢疾病中的作用
- 批准号:
MR/Y013891/1 - 财政年份:2024
- 资助金额:
$ 6.52万 - 项目类别:
Research Grant
ESTABLISHING THE ROLE OF ADIPOSE TISSUE INFLAMMATION IN THE REGULATION OF MUSCLE MASS IN OLDER PEOPLE
确定脂肪组织炎症在老年人肌肉质量调节中的作用
- 批准号:
BB/Y006542/1 - 财政年份:2024
- 资助金额:
$ 6.52万 - 项目类别:
Research Grant
Canadian Alliance of Healthy Hearts and Minds: Dissecting the Pathways Linking Ectopic Adipose Tissue to Cognitive Dysfunction
加拿大健康心灵联盟:剖析异位脂肪组织与认知功能障碍之间的联系途径
- 批准号:
479570 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Operating Grants
Determinants of Longitudinal Progression of Adipose Tissue Inflammation in Individuals at High-Risk for Type 2 Diabetes: Novel Insights from Metabolomic Profiling
2 型糖尿病高危个体脂肪组织炎症纵向进展的决定因素:代谢组学分析的新见解
- 批准号:
488898 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Operating Grants
Activation of human brown adipose tissue using food ingredients that enhance the bioavailability of nitric oxide
使用增强一氧化氮生物利用度的食品成分激活人体棕色脂肪组织
- 批准号:
23H03323 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of new lung regeneration therapies by elucidating the lung regeneration mechanism of adipose tissue-derived stem cells
通过阐明脂肪组织干细胞的肺再生机制开发新的肺再生疗法
- 批准号:
23K08293 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A study on the role of brown adipose tissue in the development and maintenance of skeletal muscles
棕色脂肪组织在骨骼肌发育和维持中作用的研究
- 批准号:
23K19922 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Adipose Tissue T Cell Polarization and Metabolic Health in Persons Living with HIV
HIV 感染者的脂肪组织 T 细胞极化和代谢健康
- 批准号:
10619176 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation
下丘脑腹内侧区的雌激素信号调节脂肪组织代谢适应
- 批准号:
10604611 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别:
Obesity and Childhood Asthma: The Role of Adipose Tissue
肥胖和儿童哮喘:脂肪组织的作用
- 批准号:
10813753 - 财政年份:2023
- 资助金额:
$ 6.52万 - 项目类别: